Department of Health and Human Services

Part 1. Overview Information

Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Institute of Neurological Disorders and Stroke (NINDS)

Funding Opportunity Title
Translational Efforts to Advance Gene-based Therapies for Ultra-Rare Neurological and Neuromuscular Disorders (U01 - Clinical Trial Optional)
Activity Code

U01 Research Project – Cooperative Agreements

Announcement Type
New
Related Notices

None

Funding Opportunity Announcement (FOA) Number
PAR-22-030
Companion Funding Opportunity
PAR-22-028 , X01 Resource Access Program
Assistance Listing Number(s)
93.853
Funding Opportunity Purpose

The Ultra-Rare Gene-Based Therapy (URGenT) network supports Investigational New Drug (IND)-enabling studies and planning activities for First-in-Human (FIH) clinical testing of gene-based or transcript-directed therapeutics, such as oligonucleotides and viral-based gene therapies, for ultra-rare neurological or neuromuscular disorders. The goal of this funding opportunity announcement (FOA) is to accelerate the development of a promising clinical candidate with robust biological rationale and demonstrated proof of concept (POC) data for the intended approach in a model system relevant to a specified patient population towards an IND filing and the initiation of a clinical trial.

Key Dates

Posted Date
November 09, 2021
Open Date (Earliest Submission Date)
November 22, 2021
Letter of Intent Due Date(s)

30 days prior to the application due date.

Application Due Dates Review and Award Cycles
New Renewal / Resubmission / Revision (as allowed) AIDS Scientific Merit Review Advisory Council Review Earliest Start Date
December 22, 2021 December 22, 2021 Not Applicable March 2022 May 2022 July 2022
February 09, 2022 February 09, 2022 Not Applicable July 2022 October 2022 December 2022
June 09, 2022 June 09, 2022 Not Applicable November 2022 January 2023 April 2023
October 08, 2022 October 08, 2022 Not Applicable March 2023 May 2023 July 2023
February 09, 2023 February 09, 2023 Not Applicable July 2023 October 2023 December 2023
June 09, 2023 June 09, 2023 Not Applicable November 2023 January 2024 April 2024
October 10, 2023 October 10, 2023 Not Applicable March 2024 May 2024 July 2024
February 08, 2024 February 08, 2024 Not Applicable July 2024 October 2024 December 2024
June 07, 2024 June 07, 2024 Not Applicable November 2024 January 2025 April 2025

All applications are due by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on the listed date(s).

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

Expiration Date
June 08, 2024
Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide,except where instructed to do otherwise (in this FOA or in a Notice from NIH Guide for Grants and Contracts ).

Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.

Applications that do not comply with these instructions may be delayed or not accepted for review.

There are several options available to submit your application through Grants.gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

  1. Use the NIH ASSIST system to prepare, submit and track your application online.
  2. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants.gov and eRA Commons to track your application. Check with your institutional officials regarding availability.

  3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.


  4. Table of Contents

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

This funding opportunity announcement (FOA) is part of the NINDS Ultra-Rare Gene-based Therapy (URGenT) network. The mission of URGenT is to support and facilitate the development of gene-based or transcript-directed therapeutic agents with compelling proof-of-concept (POC) data towards First-in-Human (FIH) clinical trials for individuals suffering from severely debilitating or life-threatening ultra-rare neurological diseases. Specifically, this FOA will support projects ready to complete Investigational New Drug (IND)-enabling studies and initiate clinical trial planning activities. Successful projects ending with an IND cleared by FDA will be eligible to apply for funding to conduct a FIH clinical trial supported by URGenT network resources.

Applicants must have identified and characterized a clinical therapeutic candidate as supported by robust POC data for the intended therapeutic approach and specific disease. The objective of this program is to support activities, such as IND-enabling safety/toxicology studies, pharmacodynamic and pharmacokinetic (PK/PD) studies, to support initial dosing in humans, development of a clinical protocol, clinical end-point assay development, assembly of a research IND application, and clinical trial planning and preparedness activities. This is a milestone-driven cooperative agreement program involving participation of NIH program staff and external subject matter experts (SMEs) in the development of the project plan and monitoring of research progress.

Background

In the United States, a rare disease is defined as a condition that affects fewer than 200,000 people in the United States, based on the definition created by Congress in the Orphan Drug Act of 1983 and adopted by the FDA. Ultra-rare diseases affect substantially fewer people, less than or equal to 6,000; in the U.S., this equates to as few or fewer than one in 50,000 people. Approximately 95% of rare diseases, including ultra-rare diseases, have no FDA-approved therapeutic available and an estimated 80% of rare diseases have an identified genetic origin. These rare diseases are often due to pathogenic variants in a single gene that alter gene product function. Many rare and ultra-rare diseases are caused by different pathogenic variants, some of which may be unique to a single individual or to a very small number of individuals. Cumulatively, these diseases represent a large unmet medical need as there are few available effective treatments and limited commercial incentive for therapeutic development.

The NINDS Ultra-Rare Gene-based Therapy (URGenT) network addresses challenges within ultra-rare disease communities by facilitating and supporting the development of tailored therapeutic interventions using established precision medicine platforms for the treatment of individuals diagnosed with a debilitating and often fatal, ultra-rare neurological and/or neuromuscular disease. Due to the urgency of these individuals’ conditions, rapid intervention in the clinical course of disease is critical. Therefore, the selection of a viable therapeutic approach will require the ability to customize the design, testing, and delivery of these interventions.

URGenT is poised to leverage nonclinical and manufacturing data from one project to another to enable the continuous reassessment of best development practices and clinical outcomes data. This would make a platform approach to therapeutic development more accessible to ultra-rare disease communities and applicable to a broader range of diseases. In addition, this approach aims to facilitate regulatory harmonization when possible and bring therapeutic interventions to individuals sooner.

The design of early-phase clinical trials for gene-based or transcript-directed therapies for ultra-rare patient populations often differs from the design of clinical trials for other types of therapies and relies upon unique collaborations to be successful. Successful completion of the funded project is expected to lead into a clinical trial, which will be supported by mechanisms targeted to URGenT U01 award recipients through limited competition.

Research Scope

URGenT provides multiple pathways into the network for studies that propose to utilize URGenT infrastructure and resources, culminating in submission of an IND package to the FDA and preparation for a subsequent application to conduct a FIH clinical trial. One path allows direct access to resources, PAR-22-028 Ultra-Rare Gene-based Therapy (URGenT) Network Resource Access (Clinical Trial Not Allowed)(X01), for applicants proposing to conduct planning activities and/or limited nonclinical development studies with a clinical candidate therapeutic to generate additional data (as needed) before a pre-Investigational New Drug (IND) meeting or submission of an IND application. Another path into the network is described in this FOA and seeks applications proposing to conduct formal IND-enabling activities and clinical trial planning activities.

The program will support nonclinical IND-enabling development activities, such as cGMP manufacturing and safety/toxicology studies, of a clinical therapeutic that will lead to the assembly and submission of a research IND application and the initiation of clinical trial planning activities.

Since a single ultra-rare disease may be caused by many different pathogenic variants, some of which may be unique to a very small numbers of patients, the selection of a viable therapeutic approach will require the ability to customize the design, testing, and delivery of these interventions. The following gene-based or transcript-directed therapeutic modalities are potentially amenable to the development of precision therapeutic approaches:

Oligonucleotide-based approaches

Oligonucleotides offer the potential to treat many genetic diseases by either ameliorating splicing pathogenic variants, promoting exon skipping, or targeting dominantly acting transcripts. Oligonucleotide-based interventions for neurological diseases include, but are not limited to antisense oligonucleotides (ASOs), small interfering RNAs (siRNA) or short hairpin RNAs (shRNA).

Viral vector-based approaches

Viral-based therapeutics (e.g., Adeno-Associated Viruses (AAVs)) and other potential vector and/or delivery vehicles, containing the correct gene construct, may be used as an in vivo therapeutic approach to replace or knockdown expression of a disease-causing gene. Alternatively, cell therapies involving ex vivo gene targeting may offer another therapeutic approach.

Genome editing-based approaches

Several platform technologies such as Zinc Finger Nucleases (ZFNs), Transcription Activator-like Effector-based Nucleases (TALENs) and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-CRISPR-associated protein systems have emerged as promising approaches to correct disease-causing pathogenic variants.

Other gene-based therapeutic approaches

Small-molecule drugs that can selectively bind RNA and modulate pre-mRNA splicing have potential as a treatment strategy for human genetic diseases. Therefore, these nucleic acid–targeted small molecules have therapeutic potential in the treatment of some ultra-rare neurological and neuromuscular diseases.

Structure

Applications submitted in response to this FOA will utilize a milestone-driven cooperative agreement (U01) mechanism to conduct nonclinical IND-enabling studies, file a research IND, and prepare for a clinical trial. Applications are expected to address objectives for both the nonclinical and clinical trial preparedness milestones and are strongly encouraged to use project management principles as appropriate.

The nonclinical and clinical trial planning milestones combined are generally expected to be completed within a total of 2 years.

For each project provided access to the network, the NINDS will assemble a customized Multi-disciplinary Project Team (MPT). The MPT will include members of the Program Director/Principal Investigator’s (PD/PI) team and additional SME consultants. The MPT will establish an overall strategy for the project with milestones, including a plan and timeline, and will develop and coordinate activities across different URGenT contract resources.

Leveraging NINDS Contract Research Resources

URGenT will provide successful applicants with access to therapeutic development resources and SME consultants. These NINDS contract resources will assist investigators to rapidly advance patient-customized therapeutics through manufacturing, nonclinical toxicology testing, and evaluation in clinical studies. A list of current URGenT resources can be found at http://www.ninds.nih.gov/Current-Research/Research-Funded-NINDS/Translational-Research/urgent-network.

Entry Requirements

Applicants that have rational POC data obtained through scientifically rigorous experimentation for a viable gene-based or transcript-directed therapeutic clinical candidate for a specified ultra-rare disease patient population that supports nonclinical and clinical development are encouraged to apply.

  • A patient or patient population has been identified with an ultra-rare neurological or neuromuscular syndrome due to a defined pathogenic variant.
  • A sufficient understanding of the pathogenic variant exists and is the basis of the proposed therapeutic approach that will allow for a plausible intervention strategy in the specified patient population.
  • The POC data establishes the feasibility and rationale for the use of the therapeutic candidate as evidenced by a pharmacologically effective dose range using appropriate assays. The POC data demonstrates scientific rigor through blinding, randomization, predetermined sample sizes, and appropriate statistical analysis.
  • The PD/PI has identified a gene-based or transcript-directed therapeutic clinical candidate supported by a substantial body of in vivo and/or in vitro data demonstrating that testing of the efficacy and preliminary safety of the candidate therapeutic in one or more model systems can mimic the planned clinical trial scenario.
  • The PD/PI has held formal pre-IND discussions with the relevant FDA division regarding a future regulatory path and other requirements needed before initiation of IND-enabling studies.
  • The PD/PI is able to provide an outline of the future clinical trial, detailing aspects such as the proposed study design, study duration, study population, primary outcomes and safety measures and data analysis methods.

This FOA encourages applications proposing plans for nonclinical development in parallel with clinical planning activities, including, but not limited to:

  • Manufacturing (i.e., technology transfer, process development, analytical methods development, small-scale, engineering runs and clinical scale cGMP manufacturing of the biological therapeutic at a CMO to be used for IND-enabling studies and FIH clinical study).
  • Qualification and/or validation of any bioassays required for IND-enabling nonclinical and clinical studies
  • IND-enabling efficacy studies with intended clinical grade product
  • IND-enabling safety and toxicology testing in relevant animal model(s) for proposed indication in compliance with Good Laboratory Practices (GLP)
  • Assessment of off-target affects as appropriate for the type of intervention under development
  • Characterization and testing for ADME (absorption, distribution, metabolism, and excretion) as basis for calculation and justification for dose extrapolation from animals to humans
  • Evaluation utility of pharmacodynamic/target engagement biomarkers associated with the therapeutic target or disease
  • Completion of all clinical trial planning activities necessary for implementation of clinical trial, including IRB
  • Preparation and submission of an IND package

Milestones

Because therapeutics development is inherently high risk, it is expected that there may be attrition as projects progress. Clear Go/No-Go milestones will be established by the MPT. The MPT will establish an overall strategy for the project with milestones, including a plan and timeline, to develop and coordinate activities across different URGenT contract resources.

These milestones will be based upon a template outline of achievements necessary to progress through therapeutic development but will be tailored to the specific therapeutic and its intended disease indication. Successful continuation of projects will be contingent upon:

  • Successful achievement of the milestones
  • Overall feasibility of project advancement, considering data that may not have been captured in the milestones
  • Additional resources needed
  • Ethical considerations

Clinical Trial Information

For applications proposing a clinical trial, note the following definitions and restrictions for this funding announcement:

  • Clinical trials are research studies in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes. For this funding announcement, only the following types of clinical trials will be supported:
    • Mechanistic trials, defined as studies designed to understand a biological or behavioral process, the pathophysiology of a disease, or the mechanism of action of an intervention (i.e., HOW an intervention works, but not IF it works or is safe).
    • Basic Experimental Studies with Humans (BESH), defined as basic research studies involving humans that seek to understand the fundamental aspects of phenomena.
  • Clinical trials that seek to answer specific questions about safety, tolerability, clinical efficacy, effectiveness, clinical management, and/or implementation of pharmacologic, behavioral, biologic, surgical, or device (invasive or non-invasive) interventions, preventive, therapeutic, and services interventions will not be supported under this Translational Efforts to Advance Gene-based Therapies for Ultra-Rare Neurological and Neuromuscular Disorders (U01) FOA. Please refer to https://www.ninds.nih.gov/Funding/Find-Funding-Opportunities to find the appropriate NIH or NINDS-specific FOA for such clinical trials. Interventional trials as part of the URGenT network will be supported through a separate mechanism.

Applicants are strongly advised to consult with NINDS Scientific/Research staff prior to submitting an application with human subjects to determine the appropriate funding opportunity.
 

Applications Not Responsive to this FOA:

Nonresponsive applications include those that involve any of the following activities:

  • Screening to identify lead therapeutic agents
  • Nonclinical studies of disease mechanism or therapeutic mechanism of action studies
  • Animal model development
  • Development of diagnostics or diagnostic devices
  • Research focused entirely on biomarkers and/or clinical endpoint development
  • Early stage projects without significant POC data that have not identified a lead clinical candidate ready for IND-directed development
  • Clinical trials that seek to answer specific questions about safety, tolerability, clinical efficacy, effectiveness, clinical management, and/or implementation of pharmacologic, behavioral, biologic, surgical, or device (invasive or non-invasive) interventions, preventive, therapeutic, and services interventions

Nonresponsive applications will be administratively withdrawn prior to review.
 

Intellectual Property Rights and Confidentiality

This program is structured so that the awardee institution retains their assignment of intellectual property (IP) rights and gains assignment of IP rights from the URGenT contractors (and thereby control the patent prosecution and licensing negotiations) for candidate therapeutics developed in this network. It is expected that the awardee institution will take responsibility for patent filings and maintenance and licensing efforts toward eventual commercialization. The PD/PI is expected to work closely with technology transfer/business development officials at his or her institution to ensure that royalty agreements, patent filings, and all other necessary IP arrangements are completed in a timely manner and that commercialization plans are developed and updated over the course of the project. Award recipients will be encouraged to identify and foster relationships with potential licensing and commercialization partners early in the drug development process, consistent with the goals of URGenT.

All SMEs will treat information as confidential and not disclose data or their assessments to third parties.

Consultation

Applicants to this FOA are strongly encouraged to consult with the Scientific/Research staff for the area of science for which they are planning to develop an application. Early contact is encouraged as it provides an opportunity for NINDS staff to discuss the scope, goals, and resources needed of the project and to provide guidance to applicants.
 

See Section VIII. Other Information for award authorities and regulations.

Section II. Award Information

Funding Instrument

Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities. See Section VI.2 for additional information about the substantial involvement for this FOA.

Application Types Allowed
New
Resubmission
Revision

The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types. Only those application types listed here are allowed for this FOA.

Clinical Trial?

Optional: Accepting applications that either propose or do not propose clinical trial(s).

Need help determining whether you are doing a clinical trial?

Funds Available and Anticipated Number of Awards

The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.

Award Budget
Application budgets are not limited but need to reflect the actual needs of the proposed project.
Award Project Period

The scope of the proposed project should determine the project period. The typical project period is expected not to exceed 2 years.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this FOA.

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

Higher Education Institutions

  • Public/State Controlled Institutions of Higher Education
  • Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

  • Hispanic-serving Institutions
  • Historically Black Colleges and Universities (HBCUs)
  • Tribally Controlled Colleges and Universities (TCCUs)
  • Alaska Native and Native Hawaiian Serving Institutions
  • Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

  • Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
  • Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

  • Small Businesses
  • For-Profit Organizations (Other than Small Businesses)

Local Governments

  • State Governments
  • County Governments
  • City or Township Governments
  • Special District Governments
  • Indian/Native American Tribal Governments (Federally Recognized)
  • Indian/Native American Tribal Governments (Other than Federally Recognized)

Federal Governments

  • Eligible Agencies of the Federal Government
  • U.S. Territory or Possession

Other

  • Independent School Districts
  • Public Housing Authorities/Indian Housing Authorities
  • Native American Tribal Organizations (other than Federally recognized tribal governments)
  • Faith-based or Community-based Organizations
  • Regional Organizations
Foreign Institutions

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed. 

Required Registrations

Applicant organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

  • Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
  • System for Award Management (SAM) – Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • eRA Commons - Applicants must have an active DUNS number to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration, but all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
  • Grants.gov – Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account.  PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Eligible Individuals (Program Director/Principal Investigator)

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

2. Cost Sharing

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

3. Additional Information on Eligibility

Number of Applications

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time.  This means that the NIH will not accept:

  • A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
  • A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
  • An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101)

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

Letter of Intent

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

  • Descriptive title of proposed activity
  • Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
  • Names of other key personnel
  • Participating institution(s)
  • Number and title of this funding opportunity

The letter of intent should be sent to:

Chris Boshoff, Ph.D.
Program Director
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1779
Email: chris.boshoff@nih.gov

Page Limitations

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed , with the following exceptions or additional requirements

For this specific FOA, the Research Strategy section is limited to 30 pages.

Instructions for Application Submission

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

SF424(R&R) Cover

All instructions in the SF424 (R&R) Application Guide must be followed.

SF424(R&R) Project/Performance Site Locations

All instructions in the SF424 (R&R) Application Guide must be followed.

SF424(R&R) Other Project Information

All instructions in the SF424 (R&R) Application Guide must be followed.

SF424(R&R) Senior/Key Person Profile

All instructions in the SF424 (R&R) Application Guide must be followed.

The proposed nonclinical activities and clinical trial planning activities must be directed by PD(s)/PI(s) with experience in the conduct of studies leading up to IND submissions and clinical trials for individuals with ultra-rare disorders. Such experience must be documented in the biosketch, including timely submission of primary publications from previous studies and/or clinical trials. The application should also indicate the prior experience of other study team members.

R&R or Modular Budget

All instructions in the SF424 (R&R) Application Guide must be followed.

R&R Subaward Budget

All instructions in the SF424 (R&R) Application Guide must be followed.

PHS 398 Cover Page Supplement

All instructions in the SF424 (R&R) Application Guide must be followed.

PHS 398 Research Plan

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Preliminary Studies: Present the major findings of the nonclinical studies that led to the pre-IND meeting with the relevant FDA division. Ensure that the data supporting the proposed study meets the NIH scientific rigor guidelines (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-103.html). If nonclinical data (e.g., animal studies) do not meet the rigor guidelines, the applicant should discuss the limitations of the data and any plans to address those gaps in knowledge through the current study design.

Discuss the potential biases and/or challenges in the feasibility of the study and how they will be addressed.

Specific Aims: The Specific Aims section should include Aims delineated for both the nonclinical and clinical trial planning activities of the project.

Research Strategy: The Research Strategy should include the entire scope of the project and provide a clear description of requested activities and/or services including:

  • Clinical Impact (Significance)
  • Biological Rationale and Profile of the Therapeutic Modality (Significance)
  • Early or Late Strategy (Approach)
  • Milestones
  • Innovation
  • Intellectual Property

Clinical Impact (Significance):

Applicants should include a brief statement of the therapeutic hypothesis that includes: the projected patient reduction of symptoms, slowing disease progression, side effects, dose administration and regimen, and sustainability of effect.

Provide a Target Product Profile (TPP) that summarizes the minimal/ideal profile of the final product and shows the ultimate goals of the proposed drug development effort, such as disease indication, patient population, delivery mode, treatment duration, treatment regimen, and standards for clinical efficacy. See examples: https://neuroscienceblueprint.nih.gov/sites/default/files/documents/Example_TPP_508C.pdf

Discuss how the therapy would be an improvement over currently available therapies. Describe the target clinical population and how treatment would be most efficacious at different stages of disease (therapeutic window).

Biological Rationale and Profile of the Therapeutic Agent (Significance):

Applicants should summarize the evidence that validates the drug target from cellular or animal models and/or related clinical studies, provide a brief summary of the rationale for the selection of the target, the level of agreement in the field regarding the target's role in disease pathogenesis, and clinical relevance of the target.

Provide the evidence that altering target activity as proposed will give desirable clinical outcomes.

Describe possible clinical trial endpoints and the availability of analytical methods. Indicate if biomarkers are available in animal models and humans to detect whether the therapy engages the target.

Applicants should discuss the disease-relevance of in vitro or in vivo models that are proposed or that have been used and whether the endpoints measured, and levels of activity observed are likely to be clinically relevant.

Studies using animal models presented to justify the choice of therapeutic target or gene-based therapeutic must be sufficiently powered, controlled, and replicated to lend a high degree of confidence in the results. Supporting preclinical data should be gathered and reported in compliance with NIH guidance on rigor and reproducibility (https://grants.nih.gov/reproducibility/index.htm#guidance).

Demonstrate that the therapeutic candidate proposed is expected to alter the activity of the putative target as intended and/or produces desired outcomes in disease models, with sufficient detail to allow reviewers to evaluate the rigor of the experimental design. Explain the choice of models, assays, and endpoints for these studies.

Demonstrate that the proposed development candidate has clinically relevant in vivo or in vitro activity, when delivered by the clinically intended route of administration, at exposure levels that can likely be achieved clinically with the proposed human dosing regimen.

Describe the in vivo (animal model) efficacy study design in detail, including the power analysis and associated assumptions for the determination of sample size, statistical handling of the data (such as criteria for data inclusion or exclusion), procedures used for blinding and randomization, and whether studies were replicated and consideration of sex as a biological variable (SBV) and the authentication of reagents.

Testing Strategy (Approach):

Indicate which activities will be conducted by the PD/PI and associated personnel and which activities will be conducted through NINDS resources.

Discuss plans to incorporate any translatable, clinically relevant biomarkers into preclinical and clinical development plan.

Include an outline that lays out each step in the critical path of the project.

Include a table with yearly milestones and quantitative successes (Go-No Go criteria).

Describe plans for data analysis and interpretation of outcomes, including what effect size would be considered minimally acceptable and clinically relevant (i.e., what constitutes a go/no go decision for advancement into FIH Clinical trial).

Explain how the project offers an approach to treating the patient population as proposed in the Target Product Profile (TPP).

Explain how the anticipated clinical testing of the therapeutic compound will be addressed including aspects such as the proposed study design, study duration, study population, primary outcomes and safety measures, and data analysis methods.

Intellectual Property:

Applicants should describe any constraints of which they are aware that could impede their use of compounds, assays, or models for research purposes and/or clinical development (e.g., certain restrictions under transfer or sharing agreements, applicants' previous or present intellectual property filings and publications, compounds with similar structures that are under patent and/or on the market, etc.) and how these issues would be addressed. If the applicant has filed pertinent patents, the applicant should indicate filing dates, the type of patent, and application status.

No IP will be held by NINDS or any of its contractors or consultants.

Letters of Support: If collaborations have been established, include letters of collaboration in the application that document the role of each collaborator. Letters should be combined into a single PDF and uploaded via the Letters of Support attachment.

Intellectual Property:

If applying from an academic institution, include a letter of support from the technology transfer official who will be managing IP and licensing associated with this project and agreement to share confidentially with NIH details of any licensing agreements related to the proposed program relevant to determining feasibility of commercialization for the proposed disease area.

If research will be performed at more than one institution, include a letter of support from each institution clarifying how IP will be shared or otherwise managed across the institutions, to ensure that the IP remains unencumbered, consistent with achieving the goals of the project.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide.

All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

Appendix:
Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

The following modifications apply:

If any FDA meetings have been held, documentation of meeting outcomes, agreements, disagreements, and action items should be summarized and included as an Appendix document. These meetings can include pre-IND meetings and, earlier in development, INitial Targeted Engagement for Regulatory Advice on CBER producTs (INTERACT) meetings. Early, nonbinding regulatory advice can be obtained from the FDA through an INTERACT meeting, which can be used to discuss issues such as a product’s early preclinical program, and/or through a pre-IND meeting prior to submission of the IND.

PHS Human Subjects and Clinical Trials Information

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered “Yes” to the question “Are Human Subjects Involved?” on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed.

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed.

Do not enter a delayed onset study.

PHS Assignment Request Form

All instructions in the SF424 (R&R) Application Guide must be followed.

3. Unique Entity Identifier and System for Award Management (SAM)

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

4. Submission Dates and Times

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time.  If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

7. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide.  Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply – Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Requests of $500,000 or more for direct costs in any year

Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact a Scientific/Research Contact at least 6 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the SF424 (R&R) Application Guide. 

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

In addition, NINDS will accept regulatory meeting minutes and transcripts, patents, and late-breaking data.

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process.  Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

For this particular announcement, note the following:

Reviewers will focus on the overall impact of the study which will also include the evaluation of the supporting data, experimental design, and all the review criteria described below.

In addition, for applications involving clinical trials: A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.

Overall Impact

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Scored Review Criteria

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

For this announcement, note the following:

How strong are the data supporting the choice of therapeutic modality for the identified genetic disease?

Is understanding of the pathogenic variant and its consequences adequate to form the basis for the proposed therapeutic approach?

Do the POC data (in vitro and/or in vivo models) support the therapeutic hypothesis for the patient population and establish a potential clinical significance for the therapeutic intervention?

Is the rationale for the selection of the target, the level of agreement in the field regarding the target's role in disease pathogenesis and clinical relevance of the target explained?

Is the explanation of route of administration, initial dose selection, and potential side effects well-justified, appropriate, and explained in enough detail to adequately determine the project’s potential risk/benefit profile?

Is the proposed therapeutic candidate expected to alter the activity of the putative target as intended and/or produces desired outcomes in disease models such as ameliorating symptoms and/or delaying disease onset?

If nonclinical data (e.g., animal studies) do not meet the rigor guidelines, how well does the application discuss the limitations of those data?

How significant an advantage does the proposed therapeutic candidate offer over other treatments under development?

What is the likelihood that completion of the research objectives will lead to a therapy (i.e., is there a clear path into the clinic)?

In addition, for applications involving clinical trials

Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

In addition, for applications involving clinical trials

With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?

Innovation

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

In addition, for applications involving clinical trials

Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

For this announcement, note the following:

Can the eligible patient population be identified based on the pathogenic variant and other common disease characteristics and clinical manifestations?

Are rigorous testing methodologies, e.g. biomarker assays, available and proposed to assess the safety and efficacy outcomes of the therapeutic for IND-enabling and subsequent clinical trials?

If the FDA has provided guidance through a pre-IND meeting, how well do the proposed studies match that guidance?

Is it feasible to scale-up the synthesis/manufacture of the proposed development candidate to levels required for proposed IND-enabling studies and future clinical trials?

Does the development plan include all the appropriate studies for obtaining an IND? Are the timelines realistic?

Are the proposed studies appropriate, feasible and consistent with the proposed TPP and late-stage nonclinical activities, and expected to advance the project to filing of an IND package within the proposed timeframe?

Is the proposed clinical therapeutic candidate expected to result in measurable clinical outcomes and would be ready for clinical testing at the conclusion of the proposed activities?

In addition, for applications involving clinical trials

Does the application adequately address the following, if applicable

Study Design

Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?

Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?

Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?

Data Management and Statistical Analysis

Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?

Environment

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

For this announcement, note the following:

How well does the project leverage the use of existing NIH tools and other resources, including partnership(s) with existing research networks?

In addition, for applications involving clinical trials

If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?

Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?

If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?

If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?

Additional Review Criteria

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

Project Timeline and Milestones

Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources?

Are the project milestones considered to be achievable and appropriate to attain the proposed project deliverables?
 

 

Study Timeline

Specific to applications involving clinical trials

Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?

Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

Protections for Human Subjects

For research that involves human subjects but does not involve one of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Individuals Across the Lifespan

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Renewals

Not Applicable.

Revisions

For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.

Additional Review Considerations

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Applications from Foreign Organizations

Not Applicable.

Select Agent Research

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3)  Genomic Data Sharing Plan (GDS).

Authentication of Key Biological and/or Chemical Resources:

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Budget and Period of Support

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NINDS, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications will receive a written critique.

Applications may undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:
  • Scientific and technical merit of the proposed project as determined by scientific peer review.
  • Availability of funds.
  • Relevance of the proposed project to program priorities.

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

Section VI. Award Administration Information

1. Award Notices

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the recipient's business official.

Recipients must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website.  This includes any recent legislation and policy applicable to awards that is highlighted on this website.

Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.

ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain “applicable clinical trials” on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm

Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the recipient must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex. This includes ensuring programs are accessible to persons with limited English proficiency. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html.

HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA.

Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.

Cooperative Agreement Terms and Conditions of Award

The following special terms of the award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Parts 75, 2 CFR Part 200, and other HHS, PHS and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, and "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the recipients is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the recipients for the project, although specific tasks and activities may be shared among the recipients and the NIH as defined below.

    • The PD/PI in collaboration with the MPT will have the primary responsibility to define research objectives and approaches and to plan, conduct, analyze and publish results, interpretations and conclusions of their studies, and for providing overall scientific and administrative leadership for the research project.
    • The PD/PI in collaboration with the MPT will oversee all aspects of the organization and execution of the studies outlined in the application and approved by NINDS.
    • Recipients have primary and lead responsibilities for the project as a whole, including any modification of study design, the conduct of the study, quality control, data analysis and interpretation, preparation of publications, and collaboration with other investigators unless otherwise provided for in these terms or by the action of the primary leadership committee.
    • Recipients will be responsible for putting all study materials and procedure manuals into the public domain. Recipients are expected to publish and publicly disseminate results, data, and other products of the study, concordant with governance policies and protocols. Publications and oral presentations of work performed under this agreement will require appropriate acknowledgment of support by the NINDS/NIH.
    • Recipients will be responsible for obtaining prior written approval of the NINDS Grants Management Specialist in consultation with the NINDS Program Officer for any change in any of the key personnel identified in the Notice of Grant Award.
    • Recipients will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.

NIH staff has substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

The Project Coordinator will have substantial programmatic involvement that is above and beyond the typical stewardship role in other awards, as described below. The Project Coordinator, with no role in stewardship of the award, will provide technical assistance, advice, coordination, and other program actions to support the recipients of the cooperative agreement during the conduct of an activity. In addition to the Project Coordinator, an NINDS Administrative Program Officer (PO) will be responsible for normal program stewardship of awards and will sign off on the grant documents and be responsible for the stewardship of the award, including monitoring implementation of the data and research resource sharing plans. The PO is named in the award notice.

The MPT will:

    • Have access to data generated under this Cooperative Agreement and may periodically review the data and administrative progress reports. Program staff may use information obtained from the data for the preparation of internal reports on the activities of the study. However, recipients will retain custody of and have primary rights to all data developed under these awards, subject to Government rights of access consistent with HHS, PHS, and NIH policies.
    • Serve as a resource to provide scientific/programmatic support during the accomplishment of the research by participating in the design of the activities, advising in the selection of sources or resources (e.g., determining where a particular reagent can be found), provision of research resources and reagents available from NINDS grantees and contractors, advising in management and technical performance, or participating in the preparation of publications.
    • Monitor progress of study milestones; as with any award, continuation, even during the period recommended for support, is contingent upon satisfactory progress. Progress will be monitored by NINDS. The schedule for these interim reviews will be based upon the duration of the clinical trial period. Continuation of funding will be dependent upon the recipient’s ability to show adequate progress towards milestone accomplishment.

3. Reporting

When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for recipients of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later.  All recipients of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000.  See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period.  The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS).  This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313).  As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available.  Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 – Award Term and Conditions for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

Application Submission Contacts

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-945-7573

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

Scientific/Research Contact(s)

Chris Boshoff, Ph.D.
Program Director
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1779
Email: chris.boshoff@nih.gov

Mario H. Skiadopoulos, Ph.D.
Program Director
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1779
Email: mario.skiadopoulos@nih.gov

Peer Review Contact(s)

Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke (NINDS)
Email: nindsreview.nih.gov@mail.nih.gov

Financial/Grants Management Contact(s)

Chief Grants Management Officer
National Institute of Neurological Disorders and Stroke (NINDS)
Email: ChiefGrantsManagementOfficer@ninds.nih.gov

Section VIII. Other Information

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Authority and Regulations

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 2 CFR Part 200, 42 CFR Part 52 and 45 CFR Part 75.

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